41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherap...

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Detalles Bibliográficos
Autores: Libero Baroni, Matteo, Sánchez Martínez, Diego|||0000-0003-4605-5325, Gutiérrez-Agüera, Francisco|||0000-0002-8620-2839, Roca Ho, Heleia|||0000-0001-7324-5234, Castellà, Maria, Zanetti, S. R.|||0000-0002-9052-8751, Velasco-Hernández, Talia|||0000-0003-2183-7443, Díaz de la Guardia, Rafael|||0000-0001-9568-6719, Castaño Cardoso, Julio|||0000-0002-0712-5856, Anguita, Eduardo|||0000-0003-1386-4943, Vives Polo, Susana|||0000-0003-2217-5285, Nomdedeu Guinot, Jose Francisco|||0000-0003-3399-346X, Lapillone, Helene, Bras, Anne E., Van Der Velden, Vincent H. J., Junca, Jordi|||0000-0003-0142-772X, Marin, Pedro, Bataller, Alex|||0000-0002-6085-2745, Esteve Reyner, Jordi|||0000-0002-8056-648X, Vick, Binje, Jeremias, Irmela|||0000-0003-1773-7677, Lopez, Angel, Sorigue, Marc|||0000-0002-0587-591X, Bueno, Clara|||0000-0003-1442-6216, Menéndez Bujan, Pablo|||0000-0001-9372-1007
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:236433
Acceso en línea:https://ddd.uab.cat/record/236433
https://dx.doi.org/urn:doi:10.1136/jitc-2020-000845
Access Level:acceso abierto
Palabra clave:T lymphocytes
Cell engineering
Immunotherapy, adoptive
Descripción
Sumario:BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative. METHODS: We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs. RESULTS: Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs. CONCLUSIONS: This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.

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